On November 24, 2009, FDA approved revisions to the INTELENCE (etravirine) labeling to include updated results through 48 weeks of dosing for the two Phase 3 trials TMC125-C206 and TMC125-C216 in treatment-experienced patients. This constitutes the required confirmatory data for Traditional approval.

The section below includes the major changes to the labeling.

Highlights

The following text depicted in bold type was added to DRUG INTERACTIONS:

Co-administration of INTELENCE™ with drugs that are substrates of CYP3A, CYP2C9, and/or CYP2C19 or are transported by P-glycoprotein may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s). (7)

Full Prescribing Information

Section 1: INDICATIONS AND USAGE was updated to include the indication is based on Week 48 analyses.

Section 5: WARNINGS AND PRECAUTIONS subsection 5.1 Severe Skin and Hypersensitivity Reactions was further revised since the September 15, 2009 action. Angioedema was added to the description of hypersensitivity reaction.

Section 6: ADVERSE REACTION was revised. Clinical adverse drug reactions (ADRs) of moderate intensity or greater (≥ Grade 2) and reported in ≥ 2% of subjects treated with INTELENCE™ and occurring at a higher rate compared to placebo (excess of 1%) are peripheral neuropathy and rash. The "Less common Adverse Reactions" subsection was updated and now includes hepatic failure, and acute renal failure.

Section 7: DRUG INTERACTIONS was updated to include information on digoxin, maraviroc and provide further clarification to the atazanavir/ritonavir and lopinavir/ritonavir interaction as follows.

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE™ may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 3). [See also Clinical Pharmacology (12.3).

Pharmacokinetics in Adults

* All HIV-1-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table 5 account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE™ with darunavir/ritonavir.

Drug Interactions

Section 12.4 Microbiology was updated to include the results of trials C206 and C216 through Week 48. Additionally virologic response by baseline number of IAS-USA Defined NNRTI substitutions, by baseline phenotype and Enfuvirtide use, and by PSS (phenotypic susceptibility score) were updated with the Week 48 results.

Section 13: NONCLINICAL TOXICOLOGY was updated to include the results of the carcinogenicity findings in mice and rats as follows:

Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg/kg were administered to mice and doses of 70, 200 and 600 mg/kg were administered to rats in the initial period of approximately 41-52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50-66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2-0.7-fold (rats).

Section 14: CLINICAL STUDIES was updated to include the 48 week results. Highlights include the following:

Of the study population who either re-used or did not use ENF, 57.4% of INTELENCE™-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL. Of the study population using ENF de novo, 67.3% of INTELENCE™-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL.

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